Antecedent Hypoglycemia, Catecholamine Depletion, and Subsequent Sympathetic Neural Responses

Abstract

Antecedent hypoglycemia is well known to impair sympathetic responses to subsequent hypoglycemia. However, it is less clear whether this occurs through altered sympathetic neural traffic or through decreased adrenal catecholamine release per se. It is also not clear whether antecedent hypoglycemia impairs sympathetic responsiveness to subsequent nonhypoglycemic sympathetic stimuli. We exposed rats to two episodes of insulin-induced hypoglycemia or sham hypoglycemia (n = 15 per group) on d -2 and -1 before exposure to transient (10 min) hypotension on d 0. Adrenal sympathetic nerve activity (SNA) was directly recorded in the conscious state and plasma catecholamine concentrations were assessed. We also examined the effect of antecedent hypoglycemia on phosphorylated and nonphosphorylated tyrosine hydroxylase (TH) protein expression as well as the expression of phenylethanolamine N-methyltransferase. Adrenal SNA was not significantly altered by antecedent hypoglycemia either at baseline of d 0 (before hypotension) or in response to hypotension. In contrast, plasma epinephrine (EPI) responsiveness was impaired by more than 50% (P = 0.025) in rats exposed to antecedent vs. sham hypoglycemia. Antecedent hypoglycemia had no effect on norepinephrine responsiveness to hypotension. In studies of adrenal tissue from separate rats, antecedent hypoglycemia decreased adrenal EPI content but did not significantly alter the expression of TH, phosphorylated TH, or phenylethanolamine N-methyltransferase. In summary, antecedent hypoglycemia impaired EPI responsiveness to subsequent hypotension despite no reduction in adrenal SNA and in association with reduced adrenal EPI content. Thus, antecedent hypoglycemia impaired responsiveness to a subsequent nonhypoglycemic sympathetic stimulus, an effect mediated at the level of the adrenal medullae.

Direct effects of recurrent hypoglycaemia on adrenal catecholamine release

“…Release of EPI (Figure 2(d)) and NE (Figure 2(e)) both increased from 1 to 30 Hz, but 100 Hz stimulation yielded no greater release. These data could indicate that IIH in previous studies 26, 27 produced maximal activation of the adrenal CAT release. Thus, to simulate the sustained and large increase in splanchnic nerve activity produced by IIH, prolonged (5 min) 30 Hz stimulus trains were also applied.…”

“…27,36,37 However, in the present experiments, no differences in the adrenal EPI and NE content were observed between Saline and RH animals subjected to four episodes of IIH (Figure 4). In addition, the weight of the RAG did not differ between Saline (25 ± 1 mg) and RH animals (24 ± 1 mg).…”

“…Nonetheless, based on in vivo recordings of splanchnic nerve activity, 26,27 we believe that these stimulus conditions closely approximate those occurring during IIH.…”

“…Stimulus train duration was either 30 s (short) to determine the frequency and voltage dependence of CAT release or 5 min (sustained) to better mimic the prolonged elevation of splanchnic nerve spike frequency observed during hypoglycaemia. 26,27 To collect blood flowing out of the LAG, the left renal vein was separated and ligated at its junctions with the vena cava and the kidney, without occluding outflow from the adrenal vein to the renal vein ( Figure S2(a)). A cannula (PE190) was inserted in this ligated segment of the renal vein to collect the outflow into cold tubes containing 5 U of heparin and 180 µg of ascorbic acid in saline.…”

“…41 In our experiments, adrenal CAT content was unchanged by RH. However, RH, 26,27,36 and even one bout of severe hypoglycaemia, 36,37,42 can produce a sustained depletion of adrenal CAT stores. This difference from our results is probably due to the higher doses of insulin used to induce hypoglycaemia in previous studies.…”